Regulation of mitochondrial biogenesis in cardiac and skeletal myocytes has important physiological consequences. In cardiomyocytes, mitochondrial content increases proportionately with contractile elements during ventricular hypertrophy induced by pressure or volume overload. In skeletal fibers, mitochondrial content can be regulated independently of contractile proteins as an adaptive response to exercise training or continuous nerve stimulation. In this proposal we seek to increase understanding of the biochemical mechanisms that regulate mitochondrial biogenesis in mammalian striated muscle cells. Results obtained in the initial phase of this project direct further research toward two classes of cellular events as possible rate-limiting steps for mitochondrial biogenesis: replication of mitochondrial DNA, and transcription of nuclear genes encoding mitochondrial proteins. The first set of specific aims of this renewal seeks to identify biochemical details of the regulation of mitochondrial DNA synthesis in muscle cells. We shall determine whether changes in the concentration or functional activity of specific proteins currently known to be involved in replication of mitochondrial DNA are evoked by stimuli that alter mitochondrial biogenesis in muscle cells. In addition, we plan to determine which of the specific steps known to be required for replication of the mitochondrial genome are altered. A second set of specific aims seeks to identify biochemical details of the transcriptional regulation of nuclear genes that encode mitochondrial proteins. We plan to identify nuclear proteins that bind to regulatory elements within such genes, and to test the hypothesis that the concentration and/or functional activity of such regulatory factors is altered by changes in muscle contractile activity. Specific attention will be directed to nuclear genes encoding inner membrane (beta F1ATPase) and matrix proteins (citrate synthase) important for oxidative metabolism, as well as genes that encode proteins involved in mitochondrial DNA replication, such as DNA polymerase gamma.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL035639-04
Application #
3349702
Study Section
Cardiovascular Study Section (CVA)
Project Start
1985-09-30
Project End
1991-09-29
Budget Start
1988-09-30
Budget End
1989-09-29
Support Year
4
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Duke University
Department
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
Li, K; Smagula, C S; Parsons, W J et al. (1994) Subcellular partitioning of MRP RNA assessed by ultrastructural and biochemical analysis. J Cell Biol 124:871-82
Bassel-Duby, R; Grohe, C M; Jessen, M E et al. (1993) Sequence elements required for transcriptional activity of the human myoglobin promoter in intact myocardium. Circ Res 73:360-6
Parsons, W J; Richardson, J A; Graves, K H et al. (1993) Gradients of transgene expression directed by the human myoglobin promoter in the developing mouse heart. Proc Natl Acad Sci U S A 90:1726-30
Ordway, G A; Li, K; Hand, G A et al. (1993) RNA subunit of mitochondrial RNA-processing enzyme is induced by contractile activity in striated muscle. Am J Physiol 265:C1511-6
Benjamin, I J; Horie, S; Greenberg, M L et al. (1992) Induction of stress proteins in cultured myogenic cells. Molecular signals for the activation of heat shock transcription factor during ischemia. J Clin Invest 89:1685-9
Annex, B H; Kraus, W E; Dohm, G L et al. (1991) Mitochondrial biogenesis in striated muscles: rapid induction of citrate synthase mRNA by nerve stimulation. Am J Physiol 260:C266-70
Annex, B H; Williams, R S (1990) Mitochondrial DNA structure and expression in specialized subtypes of mammalian striated muscle. Mol Cell Biol 10:5671-8
Morrow, N G; Kraus, W E; Moore, J W et al. (1990) Increased expression of fibroblast growth factors in a rabbit skeletal muscle model of exercise conditioning. J Clin Invest 85:1816-20
Devlin, B H; Wefald, F C; Kraus, W E et al. (1989) Identification of a muscle-specific enhancer within the 5'-flanking region of the human myoglobin gene. J Biol Chem 264:13896-901
Kraus, W E; Bernard, T S; Williams, R S (1989) Interactions between sustained contractile activity and beta-adrenergic receptors in regulation of gene expression in skeletal muscles. Am J Physiol 256:C506-14

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